bims-adipim Biomed News
on Adipose immunity and immunometabolism
Issue of 2023–05–07
twelve papers selected by
Matthew C. Sinton, University of Glasgow
  1. Adipose tissue metabolic changes in chronic kidney disease.
  2. Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification.
  3. Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice.
  4. Isolation of human cutaneous immune cells for single-cell RNA sequencing.
  5. Physiological and pathological roles of lipogenesis.
  6. Itaconate: A Potent Macrophage Immunomodulator.
  7. Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis.
  8. Spatiotemporal regulation of peripheral T cell tolerance.
  9. Integrated gene expression profiles reveal a transcriptomic network underlying the thermogenic response in adipose tissue.
  10. Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
  11. Tissue- and temporal-specific roles of extracellular ATP on T cell metabolism and function.
  12. Dendritic cell-intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity.
  1. Immunometabolism (Cobham). 2023 Apr;5(2): e00023
    Adipose tissue metabolic changes in chronic kidney disease.
    Eurico Serrano, Prashamsa Shenoy, Maria Paula Martinez Cantarin.
      Adipose tissue is a complex organ whose functions go beyond being an energy reservoir to sustain proper body energy homeostasis. Functioning as an endocrine organ, the adipose tissue has an active role in the body's metabolic balance regulation through several secreted factors generally termed as adipokines. Thus, adipose tissue dysregulation in chronic kidney disease (CKD) can have a deep impact in the pathophysiology of diseases associated with metabolic dysregulation including metabolic syndrome, insulin resistance (IR), atherosclerosis, and even cachexia. CKD is a progressive disorder linked to increased morbidity and mortality. Despite being characterized by renal function loss, CKD is accompanied by metabolic disturbances such as dyslipidemia, protein energy wasting, chronic low-grade inflammation, IR, and lipid redistribution. Thus far, the mechanisms by which these changes occur and the role of adipose tissue in CKD development and progression are unclear. Further understanding of how these factors develop could have implications for the management of CKD by helping identify pharmacological targets to improve CKD outcomes.
    Keywords:  adipokines; adiponectin; adipose tissue inflammation; chronic inflammation; chronic kidney disease; insulin resistance; leptin; protein energy wasting
    DOI:  https://doi.org/10.1097/IN9.0000000000000023
  2. Immunol Invest. 2023 May 02. 1-25
    Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification.
    Dongqin Wei, Xin Tian, Xiangyun Zhai, Chao Sun.
      Adipose tissue macrophages (ATM) are an essential type of immune cells in adipose tissue. Obesity induces the inflammation of adipose tissues, as expressed by ATM accumulation, that is more likely to become a source of systemic metabolic diseases, including insulin resistance. The process is characterized by the transcriptional regulation of inflammatory pathways by virtue of signaling molecules such as cytokines and free fatty acids. Notably, posttranslational modification (PTM) is a key link for these signaling molecules to trigger the proinflammatory or anti-inflammatory phenotype of ATMs. This review focuses on summarizing the functions and molecular mechanisms of ATMs regulating inflammation in obese adipose tissue. Furthermore, the role of PTM is elaborated, hoping to identify new horizons of treatment and prevention for obesity-mediated metabolic disease.
    Keywords:  Adipose tissue macrophages; inflammation; obesity; posttranslational modifications
    DOI:  https://doi.org/10.1080/08820139.2023.2205883
  3. Nat Commun. 2023 May 02. 14(1): 2523
    Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice.
    Fei Xiao, Haizhou Jiang, Zi Li, Xiaoxue Jiang, Shanghai Chen, Yuguo Niu, Hanrui Yin, Yousheng Shu, Bo Peng, Wei Lu, Xiaoying Li, Zhigang Li, Shujue Lan, Xiaoyan Xu, Feifan Guo.
      An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target.
    DOI:  https://doi.org/10.1038/s41467-023-38141-0
  4. STAR Protoc. 2023 Apr 28. pii: S2666-1667(23)00197-1. [Epub ahead of print]4(2): 102239
    Isolation of human cutaneous immune cells for single-cell RNA sequencing.
    Ashley A Hailer, David Wu, Abdullah El Kurdi, Michelle Yuan, Raymond J Cho, Jeffrey B Cheng.
      Single-cell RNA sequencing (scRNA-seq) allows for high-resolution analysis of transcriptionally dysregulated cell subpopulations in inflammatory diseases. However, it can be challenging to properly isolate viable immune cells from human skin for scRNA-seq due to its barrier properties. Here, we present a protocol to isolate high-viability human cutaneous immune cells. We describe steps for obtaining and enzymatically dissociating a skin biopsy specimen and isolating immune cells using flow cytometry. We then provide an overview of downstream computational techniques to analyze sequencing data. For complete details on the use and execution of this protocol, please refer to Cook et al. (2022)1 and Liu et al. (2022).2.
    Keywords:  Cell Isolation; Flow Cytometry/Mass Cytometry; Immunology; Molecular Biology; RNAseq; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2023.102239
  5. Nat Metab. 2023 May 04.
    Physiological and pathological roles of lipogenesis.
    Yong Geun Jeon, Ye Young Kim, Gung Lee, Jae Bum Kim.
      Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.
    DOI:  https://doi.org/10.1038/s42255-023-00786-y
  6. Inflammation. 2023 May 04.
    Itaconate: A Potent Macrophage Immunomodulator.
    Zeyu Li, Wenbin Zheng, Wen Kong, Tianshu Zeng.
      With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.
    Keywords:  immunity; inflammation; itaconate.; macrophage; metabolism
    DOI:  https://doi.org/10.1007/s10753-023-01819-0
  7. Mol Metab. 2023 Apr 28. pii: S2212-8778(23)00065-0. [Epub ahead of print] 101731
    Semaphorin 4B is an ADAM17-cleaved adipokine that inhibits adipocyte differentiation and thermogenesis.
    Abdulbasit Amin, Marina Badenes, Johanna Tüshaus, Érika de Carvalho, Emma Burbridge, Pedro Faísca, Květa Trávníčková, André Barros, Stefania Carobbio, Pedro M Domingos, Antonio Vidal-Puig, Luís F Moita, Sarah Maguire, Kvido Stříšovský, Francisco J Ortega, José Manuel Fernández-Real, Stefan F Lichtenthaler, Colin Adrain.
       OBJECTIVE: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis.
    METHODS: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology.
    RESULTS: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues, that acts to inhibit adipocyte differentiation and dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to dampen the expression of genes involved in adipogenesis, thermogenesis, and lipid uptake, storage and catabolism.
    CONCLUSIONS: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that modulates energy balance in adipocytes by inhibiting adipocyte differentiation, thermogenesis and lipid catabolism.
    Keywords:  ADAM17/TACE; Adipose tissue; Beta-adrenoceptor signalling; Cold challenge; Metabolism; Obesity; Semaphorin4B Sema4b; Thermogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2023.101731
  8. Science. 2023 May 05. 380(6644): 472-478
    Spatiotemporal regulation of peripheral T cell tolerance.
    Chrysothemis C Brown, Alexander Y Rudensky.
      The incomplete removal of T cells that are reactive against self-proteins during their differentiation in the thymus requires mechanisms of tolerance that prevent their effector function within the periphery. A further challenge is imposed by the need to establish tolerance to the holobiont self, which comprises a highly complex community of commensal microorganisms. Here, we review recent advances in the investigation of peripheral T cell tolerance, focusing on new insights into mechanisms of tolerance to the gut microbiota, including tolerogenic antigen-presenting cell types and immunomodulatory lymphocytes, and their layered ontogeny that underlies developmental windows for establishing intestinal tolerance. While emphasizing the intestine as a model tissue for studying peripheral T cell tolerance, we highlight overlapping and distinct pathways that underlie tolerance to self-antigens versus commensal antigens within a broader framework for immune tolerance.
    DOI:  https://doi.org/10.1126/science.adg6425
  9. Sci Rep. 2023 May 04. 13(1): 7266
    Integrated gene expression profiles reveal a transcriptomic network underlying the thermogenic response in adipose tissue.
    Jordi Rodó, Miquel Garcia, Estefania Casana, Sergio Muñoz, Claudia Jambrina, Victor Sacristan, Sylvie Franckhauser, Ignasi Grass, Veronica Jimenez, Fatima Bosch.
      Obesity and type 2 diabetes are two closely related diseases representing a serious threat worldwide. An increase in metabolic rate through enhancement of non-shivering thermogenesis in adipose tissue may represent a potential therapeutic strategy. Nevertheless, a better understanding of thermogenesis transcriptional regulation is needed to allow the development of new effective treatments. Here, we aimed to characterize the specific transcriptomic response of white and brown adipose tissues after thermogenic induction. Using cold exposure to induce thermogenesis in mice, we identified mRNAs and miRNAs that were differentially expressed in several adipose depots. In addition, integration of transcriptomic data in regulatory networks of miRNAs and transcription factors allowed the identification of key nodes likely controlling metabolism and immune response. Moreover, we identified the putative role of the transcription factor PU.1 in the regulation of PPARγ-mediated thermogenic response of subcutaneous white adipose tissue. Therefore, the present study provides new insights into the molecular mechanisms that regulate non-shivering thermogenesis.
    DOI:  https://doi.org/10.1038/s41598-023-33367-w
  10. Sci Adv. 2023 May 03. 9(18): eadf0138
    Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
    Ramya S Kuna, Avi Kumar, Karl A Wessendorf-Rodriguez, Hector Galvez, Courtney R Green, Grace H McGregor, Thekla Cordes, Reuben J Shaw, Robert U Svensson, Christian M Metallo.
      Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied 13C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.
    DOI:  https://doi.org/10.1126/sciadv.adf0138
  11. Immunometabolism (Cobham). 2023 Apr;5(2): e00025
    Tissue- and temporal-specific roles of extracellular ATP on T cell metabolism and function.
    Igor Santiago-Carvalho, Alma Banuelos, Henrique Borges da Silva.
      The activation and function of T cells is fundamental for the control of infectious diseases and cancer, and conversely can mediate several autoimmune diseases. Among the signaling pathways leading to T cell activation and function, the sensing of extracellular adenosine triphosphate (eATP) has been recently appreciated as an important component. Through a plethora of purinergic receptors, most prominently P2RX7, eATP sensing can induce a wide variety of processes in T cells, such as proliferation, subset differentiation, survival, or cell death. The downstream roles of eATP sensing can vary according to (a) the T cell subset, (b) the tissue where T cells are, and (c) the time after antigen exposure. In this mini-review, we revisit the recent findings on how eATP signaling pathways regulate T-cell immune responses and posit important unanswered questions on this field.
    Keywords:  P2RX7; T cell memory; T cells; eATP receptors; tissue damage
    DOI:  https://doi.org/10.1097/IN9.0000000000000025
  12. JCI Insight. 2023 May 04. pii: e157948. [Epub ahead of print]
    Dendritic cell-intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity.
    Hendrik Jp van der Zande, Eline C Brombacher, Joost M Lambooij, Leonard R Pelgrom, Anna Zawistowska-Deniziak, Thiago A Patente, Graham A Heieis, Frank Otto, Arifa Ozir-Fazalalikhan, Maria Yazdanbakhsh, Bart Everts, Bruno Guigas.
      Obesity-associated metabolic inflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of dendritic cells (DCs). Here, we report that hepatic DCs from high-fat diet (HFD)-fed obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11cΔLKB1) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of T helper 17-polarizing cytokines and accumulation of hepatic IL-17A+ T helper cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11cΔLKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11cΔAMPKα1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPKalpha1 and AMPK-related salt-inducible kinase(s) signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 responses.
    Keywords:  Dendritic cells; Immunology; Metabolism; Obesity; T cells
    DOI:  https://doi.org/10.1172/jci.insight.157948
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